DESCRIPTION: Endogenous nitric oxide (NO) mediates diverse functions in neuronal transmission and plasticity. In addition to its actions as a physiological mediator, NO also participates in neurotoxic brain injury, including stroke and certain neurodegenerative processes. NO synthase (NOS) is a calmodulin dependent enzyme that is regulated by the steep gradients of Ca2+ encountered in the vicinity of open Ca2+ channels. In brain NOS is functionally coupled to Ca2+ influx through N-methyl-D-glutamate (NMDA) type glutamate receptors, whereas other Ca2+ pools are poorly linked to NOS. A fundamental understanding of NO actions in brain requires identification of the functional connection of NNOS with NMDA receptors. In an effort to address this important question, this laboratory has initiated a program of cell biological studies of NOS disposition in brain. This work demonstrates that the subcellular localization of NNOS is mediated by an unusual bivalent PDZ protein motif. This NNOS PDZ domain contains a conserved binding pocket that associates with the C-termini of certain proteins including CAPON and phosphofructokinase. On the other hand, an extended "P-finger" of the NNOS PDZ domain binds to PSD-95 and PSD-93, postsynaptic density proteins that mediate synaptic clustering of NMDA receptors.